Experimental allergic encephalomyelitis (EAE), a prototype model for multiple sclerosis (MS) and organ-specific autoimmunity in general, is mediated by activated CD4+T cells. Activation within peripheral lymphoid tissue appears necessary for migration and entry into the CNS. Since T cells within CNS inflammation express activation markers and CNS accessory cells (astrocytes, microglia, and endothelial cells) can express class II in inflammatory lesions, it is thought T cell activation within the CNS is necessary for tissue destruction. Costimulation has become recognized as a pivotal event in T cell activation, determining the functional outcome of the T cell interaction with antigen, as activation without costimulation leads to a state of tolerance (anergy). Recent studies demonstrate that B7-l and B7-2, cell surface glycoproteins expressed on APC, are potent costimulatory molecules for the activation of CD4+T cells through the interaction their receptors, CD28 and CTLA4. Antigen presentation in the absence of the B7:CD28/CTLA4 costimulation in vitro can lead to anergy. The role of B7:CD28/CTLA4 costimulation in the regulation of normal and autoimmune responses in vivo is not clear. We hypothesize that B7:CD28/CTLA4 costimulation is important in the regulation of T cells mediating EAE. Peripheral activation through B7:CD28/CTLA4 costimulation may be necessary for migration and entry into the CNS. Expression of B7 costimulatory molecules by CNS accessory cells may determine whether or not tissue destruction will occur. The goal of this research program is to analyze the physiologic function of B7-l and B7-2 in vivo in EAE.
The specific aims of this proposal are to: (l) examine B7-l and B7-2 expression in normal mice and mice with EAE by immunohistochemistry and in situ hybridization, determining whether CNS accessory cells express B7 costimulatory molecules. (2) To examine the physiologic -effects of B7 deficiency in the regulation of EAE, through the study of B7-deficient mice generated by using homologous recombination and embryonic stem cell technologies. (3) To determine how constitutive expression of B7-2 influences T cell mediated autoimmunity by developing transgenic mice that selectively overexpress B7-2 in the CNS. The proposed studies will provide valuable information regarding the role of B7- l and B7-2 in CNS autoimmunity, which may give insight into the rational development of pharmacologic means to modulate T cell activation in diseases such as MS.
